Glucokinase (GK) is one of four hexokinases found in mammals [Colowick, S. P., in The Enzymes, Vol. 9 (P. Boyer, ed.) Academic Press, New York, N.Y., pages 1-48, 1973]. The hexokinases catalyze the first step in the metabolism of glucose, i.e., the conversion of glucose to glucose-6-phosphate. Glucokinase has a limited cellular distribution, being found principally in pancreatic xcex2-cells and liver parenchymal cells. In addition, GK is a rate-controlling enzyme for glucose metabolism in these two cell types that are known to play critical roles in whole-body glucose homeostasis [Chipkin, S. R., Kelly, K. L., and Ruderman, N. B. in Joslin""s Diabetes (C. R. Khan and G. C. Wier, eds.), Lea and Febiger, Philadelphia, Pa., pages 97-115, 1994]. The concentration of glucose at which GK demonstrates half-maximal activity is approximately 8 mM. The other three hexokinases are saturated with glucose at much lower concentrations ( less than 1 mM). Therefore, the flux of glucose through the GK pathway rises as the concentration of glucose in the blood increases from fasting (5 mM) to postprandial (≈10-15 mM) levels following a carbohydrate-containing meal [Printz, R. G., Magnuson, M. A., and Granner, D. K. in Ann. Rev. Nutrition Vol. 13 (R. E. Olson, D. M. Bier, and D. B. McCormick, eds.), Annual Review, Inc., Palo Alto, Calif., pages 463-496, 1993]. These findings contributed over a decade ago to the hypothesis that GK functions as a glucose sensor in xcex2-cells and hepatocytes (Meglasson, M. D. and Matschinsky, F. M. Amer. J. Physiol. 246, E1-E13, 1984). In recent years, studies in transgenic animals have confirmed that GK does indeed play a critical role in whole-body glucose homeostasis. Animals that do not express GK die within days of birth with severe diabetes while animals overexpressing GK have improved glucose tolerance (Grupe, A., Hultgren, B., Ryan, A. et al., Cell 83, 69-78, 1995; Ferrie, T., Riu, E., Bosch, F. et al., FASEB J., 10, 1213-1218, 1996). An increase in glucose exposure is coupled through GK in xcex2-cells to increased insulin secretion and in hepatocytes to increased glycogen deposition and perhaps decreased glucose production.
The finding that type II maturity-onset diabetes of the young (MODY-2) is caused by loss of function mutations in the GK gene suggests that GK also functions as a glucose sensor in humans (Liang, Y., Kesavan, P., Wang, L. et al., Biochem. J. 309, 167-173, 1995). Additional evidence supporting an important role for GK in be the regulation of glucose metabolism in humans was provided by the identification of patients that express a mutant form of GK with increased enzymatic activity. These patients exhibit a fasting hypoglycemia associated with an inappropriately elevated level of plasma insulin (Glaser, B., Kesavan, P., Heyman, M. et al., New England J. Med. 338, 226-230, 1998). While mutations of the GK gene are not found in the majority of patients with type II diabetes, compounds that activate GK and, thereby, increase the sensitivity of the GK sensor system will still be useful in the treatment of the hyperglycemia characteristic of all type II diabetes. Glucokinase activators will increase the flux of glucose metabolism in xcex2-cells and hepatocytes, which will be coupled to increased insulin secretion. Such agents would be useful for treating type II diabetes.
This invention provides an amide selected from the group consisting of a compound of the formula: 
wherein X is 
R is perfluoro-lower alkyl, lower alkyl, 
xe2x80x83lower alkoxycarbonyl, a heteroaromatic ring, connected by a ring carbon atom, containing from 5 to 6 ring members with from 1 to 3 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, unsubstituted aryl containing 6 or 10 ring carbon atoms, a nitro or a lower alkyl substituted aryl, which aryl contains 6 or 10 ring carbon atoms, a saturated 5- to 6-membered cycloheteroalkyl ring, connected by a ring carbon atom, containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, or a cycloalkyl ring having 5 or 6 carbon atoms; R1 is a cycloalkyl having 5 or 6 carbon atoms; R2 is a five- or six-membered heteroaromatic ring connected by a ring carbon atom to the amide group in the remainder of the compound, which heteroaromatic ring contains from 1 to 3 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen with a first heteroatom being nitrogen adjacent to the connecting ring carbon atom, said heteroaromatic ring being unsubstituted or monosubstituted at a position on a ring carbon atom other than adjacent to said connecting carbon atom with a substituent selected from the group consisting of lower alkyl, or 
n and y independently are an integer of from 1 to 4, R4, R5 and R7 are independently hydrogen or lower alkyl, and * denotes the asymmetric carbon atom and a pharmaceutically acceptable salt thereof.
The compounds of formula I are glucokinase activators useful for increasing insulin secretion in the treatment of type II diabetes.
The compounds of formula I have the following embodiments 
wherein R, R1, R2, * and y are as above;
In the compound of formulae I, IA and IB, the xe2x80x9c*xe2x80x9d designates that the asymmetric carbon atom in the compounds with the R optical configuration being preferred. The compounds of formula I may be present in the R or as a racemic or other mixtures of compounds having the R and S optical configuration at the asymmetric carbon shown. The pure R enantiomers are preferred.
As used throughout this application, the term xe2x80x9clower alkylxe2x80x9d includes both straight chain and branched chain alkyl groups having from 1 to 7 carbon atoms, such as methyl, ethyl, propyl, isopropyl, preferably methyl and ethyl. As used herein, the term xe2x80x9chalogen or haloxe2x80x9d unless otherwise stated, designates all four halogens, i.e. fluorine, chlorine, bromine and iodine.
As used herein, perfluoro-lower alkyl means any lower alkyl group wherein all of the hydrogens of the lower alkyl group are substituted or replaced by fluoro. Among the preferred perfluoro-lower alkyl groups are trifluoromethyl, pentafluoroethyl, heptafluoropropyl, etc.
As used herein, the term xe2x80x9carylxe2x80x9d signifies xe2x80x9cpolynuclearxe2x80x9d and mononuclear unsubstituted aromatic hydrocarbon groups such as phenyl, naphthy containing either 6 or 10 carbon atoms which aryl groups in the compounds of formulae I, IA and IB are either phenyl and naphthyl. The aryl substituent can be unsubstituted or substituted, preferably monosubstituted with a nitro or lower alkyl substituted.
R can be any five- or six-membered saturated cycloheteroalkyl ring containing from 1 to 2 heteroatoms selected from the group consisting of sulfur, oxygen or nitrogen. Any such five- or six-membered saturated heterocyclic ring can be used in accordance with this invention. Among the preferred rings are morpholinyl, pyrrolidinyl, piperazinyl, piperidinyl, etc. When R is a saturated cyclic heteroacetyl ring, it is connected to the remainder of the molecule of formula I through a ring carbon atom.
The heteroaromatic ring defined by R and R2 can be five- or six-membered heteroaromatic ring having from 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur which is connected by a ring carbon to the remainder of the molecule as shown. The heteroaromatic ring defined by R2 contains a first nitrogen heteroatom adjacent to the connecting ring carbon atom and if present, the other heteroatoms can be oxygen, sulfur, or nitrogen. Among the preferred heteroaromatic rings include pyridinyl, pyrimidinyl and thiazolyl. These heteroaromatic rings which constitute R are connected via a ring carbon atom to the amide group to form the amides of formula I. The ring carbon atom of the heteroaromatic ring which is connected to the amide to form the compound of formula I does not contain any substituent. When R2 is an unsubstituted or mono-substituted five- or six-membered heteroaromatic ring, the rings contain a nitrogen heteroatom adjacent to the connecting ring carbon.
The term xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d as used herein include any salt with both inorganic or organic pharmaceutically acceptable acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid, para-toluene sulfonic acid and the like. The term xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d also includes any pharmaceutically acceptable base salt such as amine salts, trialkyl amine salts and the like. Such salts can be formed quite readily by those skilled in the art using standard techniques.
During the course of the reaction the various functional groups such as the free carboxylic acid will be protected via conventional hydrolyzable ester protecting groups. As used herein, the term xe2x80x9chydrolyzable esterxe2x80x9d designates any ester conventionally used for protecting carboxylic acids which can be hydrolyzed to yield the respective carboxyl group. Exemplary ester groups useful for those purposes are those in which the acyl moieties are derived from a lower alkanoic, aryl lower alkanoic, or lower alkane dicarboxylic acid. Among the activated acids which can be utilized to form such groups are acid anhydrides, acid halides, preferably acid chlorides or acid bromides derived from aryl or lower alkanoic acids. Example of anhydrides are anhydrides derived from monocarboxylic acid such as acetic anhydride, benzoic acid anhydride, and lower alkane dicarboxylic acid anhydrides, e.g. succinic anhydride as well as chloro formates e.g. trichloro, ethylchloro formate being preferred.
Among the embodiments of the amides of formula I-A are those compounds where R1 is cyclopentyl compounds of formula I-A1. The embodiments of the compounds of formula I-A1 are those compounds where R2 is a 5-membered heteroaromatic ring, preferably thiazolyl. Among the embodiment of compounds of formula I-A1 are those compounds where R2 is a 5-membered heteroaromatic ring are those compounds where R is:
aryl, preferably phenyl;
aryl substituted with a nitro group, preferably nitro substituted phenyl;
heteroaromatic ring such as pyrimidinyl, thiazolyl and pyridinyl; or
lower alkoxy carbonyl.
Among other embodiments of the compounds of formula I-A1 are those compounds where R2 is a substituted or unsubstituted 6-membered heteroaromatic ring such as pyridinyl. Among the embodiments of compounds of formula I-A1 where R2 is a substituted or unsubstituted 6-membered heteroaromatic ring are those compounds where:
R is an unsubstituted aryl or a heteroaromatic ring, particularly pyridinyl;
R is lower alkoxy carbonyl; or
R is perfluoro-lower alkyl.
Among the embodiments of the compounds of formula I-B are those compounds wherein R1 is cyclopentyl [compounds of formula I-B1]. Among the embodiments of compounds of formula I-B1 are those compounds where R2 is a 5-membered heteroaromatic ring, preferably unsubstituted or substituted thiazolyl, with preferred embodiments being those compounds where R is a
nitro substituted aryl such as nitro substituted phenyl;
aryl such as phenyl;
lower alkyl;
perfluoro-lower alkyl; or
e) 
where R4 and R5 are as above.
The compounds of formula I which are the compounds of formulae I-A and I-B are both prepared from the compound of the formula: 
where R3 taken together with its attached oxygen atom forms a hydrolyzable ester protecting group.
In accordance with an embodiment of this invention, the compound of formula II is converted to the compound of formula I-A via the following reaction scheme: 
wherein R, R1, R2 and y are as above and R3 taken together with its attached oxygen atom forms a hydrolyzable ester protecting group.
In the first step of this reaction, the compound of formula II is alkylated with the compound of formula IV to form the compound of formula V. Any conventional method of alkylating the alpha carbon atom of an organic acid ester with an alkyl bromide or iodide can be utilized to effect this conversion to produce the compound of formula V. In the next step of this reaction, the compound of formula V is hydrolyzed so as to remove the ester protecting group R3. Any conventional method of ester hydrolysis can be utilized. Among the preferred methods is by treating the compound of formula V with lithium hydroxide in a mixed solvent of water and tetrahydrofuran. On the other hand, sodium hydroxide in methanol or other lower alkanols can be utilized to effect this hydrolysis. The compound of formula VI is converted to the compound of formula VII by reducing the nitro group to an amine group. Any conventional method of reducing a nitro to an amine group can be utilized in carrying out this reaction. Preferably, this reduction can be carried out by treating the compound of formula VI with hydrogen in the presence of a palladium on a carbon catalyst. Any of the conventional conditions for hydrogenation can be utilized in effecting this reduction. Hydrogenation in the presence of a palladium on carbon catalyst will not effect the carboxylic acid group on the compound of formula VI. The compound of formula VII is then converted to the compound of formula VIII by reacting the compound of formula VII with the compound of formula IX to acylate the free amino group. The compound of formula IX is an acid chloride and any conventional method of reacting an acid chloride with a primary amine can be utilized to effect this reaction. The compound of formula VIII is converted to the compound of formula I-A via reaction with the primary amine of formula X. Any conventional method of coupling a carboxylic acid such as the compound of formula VIII with a primary amine such as the compound of formula X produce an amide, i.e., the compound of formula I-A can be utilized to affect this coupling reaction.
The compound of formula I-B can be produced from the compound of formula VI above via the following reaction scheme: 
wherein R, R1, R2 and y are as above.
With respect to producing the sulfonamides, the compound of formula VI, as prepared by the aforementioned method, is utilized as a starting material. In this procedure, the compound of formula VI is reacted with the compound of formula X to produce the compound of formula XI. This reaction is carried out in the same manner as set forth with respect to the conversion of the compound of formula VIII to the compound of the formula I-A utilizing any conventional means of amide coupling. In the next step, the compound of formula XI is reduced via a hydrogenation in the presence of a hydrogenation catalyst such as palladium on carbon. This reaction is carried out in the same manner as previously described in connection with the hydrogenation of the compound of formula VI to the compound of formula VII. The compound of formula XII is then reacted with the compound of formula XV to produce the compound of formula I-B. This reaction is carried out by coupling the amino group of the compound of formula XII with the sulfonyl chloride of formula XV to produce the sulfonamides of formula I-B. In carrying out this coupling reaction of a sulfonyl chloride with an amine, any conventional method for forming sulfonamides from sulfonyl chlorides and amines can be utilized. In this manner, the compound of formula I-B is produced.
If it is desired to produce the R enantiomer of the compound of formula I free of the other enantiomer, the compound of formula VI can be separated into this isomer from its racemate by any conventional chemical means. Among the preferred chemical means is to react the compound of formula VI with an optically active base. Any conventional optically active base can be utilized to carry out this resolution. Among the preferred optically active bases are the optically active amine bases such as alpha-methylbenzylamine, quinine, dehydroabietylamine and alpha-methylnaphthylamine. Any of the conventional techniques utilized in resolving organic acids with optically active organic amine bases can be utilized in carrying out this reaction.
In the resolution step, the compound of formula VI is reacted with the optically active base in an inert organic solvent medium to produce salts of the optically active amine with both the R and S isomers of the compound of formula VI. In the formation of these salts, temperatures and pressure are not critical and the salt formation can take place at room temperature and atmospheric pressure. The R and S salts can be separated by any conventional method such as fractional crystallization. By means of measuring the optical rotation of the crystallized acid of formula VI, one can obtain the configuration of this crystalline material. If this crystallized acid has a negative rotation, then this crystallized acid has the R configuration. After crystallization, each of the salts can be converted to the respective compounds of formula VI in the R and S configuration by hydrolysis with an acid. Among the preferred acids are dilute aqueous acids, i.e., from about 0.001N to 2N aqueous acids, such as aqueous sulfuric or aqueous hydrochloric acid. The configuration of formula VI which is produced by this method of resolution is carried out throughout the entire reaction scheme to produce the desired R of formula I. The separation of R and S isomers can also be achieved using an enzymatic ester hydrolysis of any lower alkyl esters corresponding to the compound of the formula VI (see, for example, Ahmar, M.; Girard, C.; Bloch, R., Tetrahedron Lett, 1989, 7053), which results in the formation of corresponding chiral acid and chiral ester. The ester and the acid can be separated by any conventional method of separating an acid from an ester. The preferred method of resolution of racemates of the compounds of the formula VI is via the formation of corresponding diastereomeric esters or amides. These diastereomeric esters or amides can be prepared by coupling the carboxylic acids of the formula VI with a chiral alcohol, or a chiral amine. This reaction can be carried out using any conventional method of coupling a carboxylic acid with an alcohol or an amine. The corresponding diastereomers of compounds of the formula VI can then be separated using any conventional separation methods. The resulting pure diastereomeric esters or amides can then be hydrolyzed to yield the corresponding pure R and S isomers. The hydrolysis reaction can be carried out using any conventional method to hydrolyze an ester or an amide without racemization.
All of the compounds described in the Examples activated glucokinase in vitro in accordance with the assay described in Example A.